High plasma cholesterol levels, a major risk factor for atherosclerosis, can be reduced by inhibiting lipoprotein production; however, this is associated with steatosis. We showed that over expression of miR-30c lowers diet- induced hypercholesterolemia and atherosclerosis in C57BL/6J wild type and Apoe?/? mice. Conversely, inhibition of hepatic miR-30c increased plasma cholesterol and atherosclerosis. Based on these exciting published data, we hypothesize that endogenous miR-30c is an important regulator of lipid metabolism and that miR-30c deficiency will enhance plasma and tissue lipids, plasma cytokines and atherosclerosis. We will evaluate this hypothesis using double knockout (DKO) Mir30c1?/?;Mir30c2?/? and triple KO Mir30c1?/?;Mir30c2?/?;Apoe?/? mice fed chow and western diets with and without fructose. Next, we will establish the direct and specific role of miR-30c in the development of hypercholesterolemia and early and advanced atherosclerotic lesions by re-expressing miR-30c in the liver and spleen of these knockout mice using different strategies. Further, using similar knockout and re-expression strategies, we will elucidate physiological mechanisms (hepatic lipoprotein production, de novo lipogenesis and macrophage cytokine production) involved in the regulation of hypercholesterolemia, steatosis, inflammatory response and atherosclerosis by miR-30c. Moreover, we will evaluate the molecular hypothesis that miR-30c deficiency deregulates MTP, LPGAT1 and ELOVL5 in hepatocytes; and IKK? in macrophages to cause hypercholesterolemia, steatosis, and pro-inflammatory cytokine production. These studies will establish the importance of endogenous miR-30c in the regulation of plasma and tissue lipids and cytokine production, and will elucidate physiological, biochemical and molecular mechanisms involved in the regulation of various biological pathways by miR-30c. At the end, these studies will furnish novel information concerning the protective role of whole body as well as liver- and macrophage-specific miR-30c against diet-induced metabolic disorders.